Emergence and adaptation of the cellular machinery directing antigenic variation in the African trypanosome

TY - JOUR

T1 - Emergence and adaptation of the cellular machinery directing antigenic variation in the African trypanosome

AU - Faria, Joana

AU - Briggs, Emma M

AU - Black, Jennifer A

AU - McCulloch, Richard

N1 - © 2022 The Authors.

PY - 2022/12

Y1 - 2022/12

N2 - Survival of the African trypanosome within its mammalian hosts, and hence transmission between hosts, relies upon antigenic variation, where stochastic changes in the composition of their protective variant-surface glycoprotein (VSG) coat thwart effective removal of the pathogen by adaptive immunity. Antigenic variation has evolved remarkable mechanistic complexity in Trypanosoma brucei, with switching of the VSG coat executed by either transcriptional or recombination reactions. In the former, a single T. brucei cell selectively transcribes one telomeric VSG transcription site, termed the expression site (ES), from a pool of around 15. Silencing of the active ES and activation of one previously silent ES can lead to a co-ordinated VSG coat switch. Outside the ESs, the T. brucei genome contains an enormous archive of silent VSG genes and pseudogenes, which can be recombined into the ES to execute a coat switch. Most such recombination involves gene conversion, including copying of a complete VSG and more complex reactions where novel 'mosaic' VSGs are formed as patchworks of sequences from several silent (pseudo)genes. Understanding of the cellular machinery that directs transcriptional and recombination VSG switching is growing rapidly and the emerging picture is of the use of proteins, complexes and pathways that are not limited to trypanosomes, but are shared across the wider grouping of kinetoplastids and beyond, suggesting co-option of widely used, core cellular reactions. We will review what is known about the machinery of antigenic variation and discuss if there remains the possibility of trypanosome adaptations, or even trypanosome-specific machineries, that might offer opportunities to impair this crucial parasite-survival process.

AB - Survival of the African trypanosome within its mammalian hosts, and hence transmission between hosts, relies upon antigenic variation, where stochastic changes in the composition of their protective variant-surface glycoprotein (VSG) coat thwart effective removal of the pathogen by adaptive immunity. Antigenic variation has evolved remarkable mechanistic complexity in Trypanosoma brucei, with switching of the VSG coat executed by either transcriptional or recombination reactions. In the former, a single T. brucei cell selectively transcribes one telomeric VSG transcription site, termed the expression site (ES), from a pool of around 15. Silencing of the active ES and activation of one previously silent ES can lead to a co-ordinated VSG coat switch. Outside the ESs, the T. brucei genome contains an enormous archive of silent VSG genes and pseudogenes, which can be recombined into the ES to execute a coat switch. Most such recombination involves gene conversion, including copying of a complete VSG and more complex reactions where novel 'mosaic' VSGs are formed as patchworks of sequences from several silent (pseudo)genes. Understanding of the cellular machinery that directs transcriptional and recombination VSG switching is growing rapidly and the emerging picture is of the use of proteins, complexes and pathways that are not limited to trypanosomes, but are shared across the wider grouping of kinetoplastids and beyond, suggesting co-option of widely used, core cellular reactions. We will review what is known about the machinery of antigenic variation and discuss if there remains the possibility of trypanosome adaptations, or even trypanosome-specific machineries, that might offer opportunities to impair this crucial parasite-survival process.

KW - Animals

KW - Variant Surface Glycoproteins, Trypanosoma/genetics

KW - Antigenic Variation/genetics

KW - Trypanosoma/genetics

KW - Trypanosoma brucei brucei/genetics

KW - Genome

KW - Mammals/genetics

U2 - 10.1016/j.mib.2022.102209

DO - 10.1016/j.mib.2022.102209

M3 - Article

C2 - 36215868

SN - 1369-5274

VL - 70

SP - 102209

JO - Current Opinion in Microbiology

JF - Current Opinion in Microbiology

M1 - 102209

ER -